Abstract
Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer’s disease (AD). In contrast to these failures, acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors slow the clinical progression of the disease and randomized, placebo-controlled trials in prodromal and mild to moderate AD patients have shown AChE inhibitor anti-neurodegenerative benefits in the cortex, hippocampus, and basal forebrain. CNS neurodegeneration and atrophy are now recognized as biomarkers of AD according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria and recent evidence shows that these markers are among the earliest signs of prodromal AD, before the appearance of amyloid. The current AChE inhibitors (donepezil, rivastigmine, and galantamine) have short-acting mechanisms of action that result in dose-limiting toxicity and inadequate efficacy. Irreversible AChE inhibitors, with a long-acting mechanism of action, are inherently CNS selective and can more than double CNS AChE inhibition possible with short-acting inhibitors. Irreversible AChE inhibitors open the door to high-level CNS AChE inhibition and improved anti-neurodegenerative benefits that may be an important part of future treatments to more effectively prevent, delay the onset, or slow the progression of AD.
Highlights
Alzheimer’s disease (AD) is a severe progressive neurodegenerative disease
The purpose of this review is to explore the anti-neurodegenerative benefits of acetylcholinesterase (AChE, EC 3.1.1.7) and to suggest irreversible CNS-selective AChE inhibition for improved intervention in AD-related neurodegeneration
AD has been traditionally defined on the basis of three classical neuropathological changes in the brains of AD patients
Summary
Hundreds of clinical trials and billions of dollars seeking successful treatment or prevention have been guided by the “amyloid cascade” hypothesis [1], but this effort has produced no interventions that effectively prevent, delay the onset, slow the progression, or arrest AD [2,3,4] In view of these failures, there is an urgent and unmet need to identify new strategies and focus on other AD-related neuropathological changes, especially those that occur in the earliest stages of the disease, before more advanced irreparable brain damage [5,6,7]. A third pathophysiological marker of AD is a severe loss of neurons in the midbrain cholinergic system that provides the major cholinergic projections to the cortex and hippocampus [9]
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